Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropeptide Y (NPY) is one of the most prominent and abundant neuropeptides in the mammalian brain where it interacts with a family of G-protein coupled receptors, including the Y(1) receptor subtype (Y(1)R). NPY-Y(1)R signalling plays a prominent role in the regulation of several behavioural and physiological functions including feeding behaviour and energy balance, sexual hormone secretion, stress response, emotional behaviour, neuronal excitability and ethanol drinking. Y(1)R expression is regulated by neuronal activity and peripheral hormones. The Y(1)R gene has been isolated from rodents and humans and it contains multiple regulatory elements that may participate in the regulation of its expression. Y(1)R expression in the hypothalamus is modulated by changes in energetic balance induced by a wide variety of conditions (fasting, pregnancy, hyperglycaemic challenge, hypophagia, diet induced obesity). Estrogens up-regulate responsiveness to NPY to stimulate preovulatory GnRH and gonadotropin surges by increasing Y(1)R gene expression both in the hypothalamus and the pituitary. Y(1)R expression is modulated by different kinds of brain insults, such as stress and seizure activity, and alteration in its expression may contribute to antidepressant action. Chronic modulation of GABA(A) receptor function by benzodiazepines or neuroactive steroids also affects Y(1)R expression in the amygdala, suggesting that a functional interaction between the GABA(A) receptor and Y(1)R mediated signalling may contribute to the regulation of emotional behaviour. In this paper, we review the state of the art concerning Y(1)R function and gene expression, including our personal contribution to many of the subjects mentioned above.
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PMID:Physiology and gene regulation of the brain NPY Y1 receptor. 1698 96

Neuropeptide Y is the ligand of a family of G-protein coupled receptors (Y(1) to Y(6)). In the thalamus, exogenous and endogenously released NPY can shorten the duration of thalamic oscillations in brain slices from P13 to P15 rats, an in vitro model of absence seizures. Here, we examine which Y receptors are involved in this modulation. Application of the Y(1) receptor agonist Leu(31)Pro(34)NPY caused a reversible reduction in the duration of thalamic oscillations (-26.6+/-7.8%), while the Y(2) receptor agonist peptideYY((3-36)) and the Y(5) receptor agonist BWX-46 did not exert a significant effect. No Y receptor agonist affected oscillation period. Application of antagonists of Y(1), Y(2) and Y(5) receptors (BIBP3226, BIIE0246 and L152,806, respectively) produced results consistent with those obtained from agonists. BIBP3226 caused a reversible disinhibition, an effect that increases oscillation duration (18.2+/-9.7%) while BIIE0246 and L152,806 had no significant effect. Expression of NPY is limited to neurons in the reticular thalamic nucleus (nRt), but Y(1) receptors are expressed in both nRt and adjacent thalamic relay nuclei. Thus, intra-nRt or nRt to relay nucleus NPY release could cause Y(1) receptor mediated inhibition of thalamic oscillations.
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PMID:NPY signaling through Y1 receptors modulates thalamic oscillations. 1719 8

We have shown that neuropeptide Y (NPY) regulates neurogenesis in the normal dentate gyrus (DG) via Y(1) receptors (Howell, O.W., Scharfman, H.E., Herzog, H., Sundstrom, L.E., Beck-Sickinger, A. and Gray, W.P. (2003) Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells. J Neurochem, 86, 646-659; Howell, O.W., Doyle, K., Goodman, J.H., Scharfman, H.E., Herzog, H., Pringle, A., Beck-Sickinger, A.G. and Gray, W.P. (2005) Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus. J Neurochem, 93, 560-570). This regulation may be relevant to epilepsy, because seizures increase both NPY expression and precursor cell proliferation in the DG. Therefore, the effects of NPY on DG precursors were evaluated in normal conditions and after status epilepticus. In addition, potentially distinct NPY-responsive precursors were identified, and an analysis performed not only of the DG, but also the caudal subventricular zone (cSVZ) and subcallosal zone (SCZ) where seizures modulate glial precursors. We show a proliferative effect of NPY on multipotent nestin cells expressing the stem cell marker Lewis-X from both the DG and the cSVZ/SCZ in vitro. We confirm an effect on proliferation in the cSVZ/SCZ of Y(1) receptor(-/-) mice and demonstrate a significant reduction in basal and seizure-induced proliferation in the DG of NPY(-/-) mice.
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PMID:Neuropeptide Y is important for basal and seizure-induced precursor cell proliferation in the hippocampus. 1731 95

Neuropeptide Y (NPY) potently suppresses absence seizures in a model of genetic generalized epilepsy, genetic absence epilepsy rats of Strasbourg (GAERS). Here we investigated the Y-receptor subtype(s) on which NPY exerts this anti-absence effect. A dual in vivo approach was used: the cumulative duration of seizures was quantified in adult male GAERS in 90-min electroencephalogram recordings following intracerebroventricular (i.c.v.) injection of: (i) subtype-selective agonists of Y1 ([Leu31Pro34]NPY, 2.5 nmol), Y2 (Ac[Leu(28,31)]NPY24-36, 3 nmol), Y5 receptors [hPP1(-17),Ala31,Aib32]NPY, 4 nmol), NPY (3 nmol) or vehicle; and following (ii) i.c.v. injection of antagonists of Y1 (BIBP3226, 20 nmol), Y2 (BIIE0246, 20 nmol) and Y5 (NPY5RA972, 20 nmol) receptors or vehicle, followed by NPY (3 nmol). Injection of the Y1- and Y5-selective agonists resulted in significantly less mean seizure suppression (37.4% and 53.9%, respectively) than NPY (83.2%; P < 0.05), while the Y2 agonist had similar effects to NPY (62.3% suppression, P = 0.57). Food intake was not increased following injection of the Y2 agonist, while significant increases in food intake were seen following NPY and the other Y-subtype agonists. Compared with vehicle, NPY injection suppressed seizures following the Y1 and Y5 antagonists (45.3% and 80.1%, respectively, P < 0.05), but not following the Y2 antagonist (5.1% suppression, P = 0.46). We conclude that NPY Y2 receptors are more important than Y1 and Y5 receptors in mediating the effect of NPY to suppress absence seizures in a genetic rat model. Y2 receptor agonists may represent targets for novel drugs against genetic generalized epilepsies without resulting in appetite stimulation.
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PMID:Neuropeptide Y suppresses absence seizures in a genetic rat model primarily through effects on Y receptors. 1733 Dec 9

Neuropeptide Y (NPY) is a 36-amino-acid peptide that attenuates seizure activity following direct infusion or adeno-associated virus (AAV)-mediated expression in the central nervous system. However, NPY activates all NPY receptor subtypes, potentially causing unwanted side effects. NPY13-36 is a C-terminal peptide fragment of NPY that primarily activates the NPY Y2 receptor, thought to mediate the antiseizure activity. Therefore, we investigated if recombinant adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 could alter limbic seizure sensitivity. Rats received bilateral piriform cortex infusions of AAV vectors that express and constitutively secrete full-length NPY (AAV-FIB-NPY) or NPY13-36 (AAV-FIB-NPY13-36). Control rats received no infusion, as we have previously shown that vectors expressing and secreting reporter genes like GFP (AAV-FIB-EGFP), as well as vectors expressing peptides that lack secretion sequences (AAV-GAL) have no effect on seizures. One week later, all animals received kainic acid (10 mg kg(-1), intraperitoneally), and the latencies to wet dog shakes and limbic seizure behaviors were determined. Although both control and vector-treated rats developed wet dog shake behaviors with similar latencies, the latencies to class III and class IV limbic seizures were significantly prolonged in both NPY- and NPY13-36-treated groups. Thus, AAV-mediated expression and constitutive secretion of NPY and NPY13-36 is effective in attenuating limbic seizures, and provides a platform for delivering therapeutic peptide fragments with increased receptor selectivity.
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PMID:Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo. 1771 67

Neuropeptide Y (NPY) is contained in at least four types of GABAergic interneurons in the dentate gyrus, many of which also contain somatostatin and give rise to the dense NPY innervation of the dentate outer molecular layer. In humans but not rats, minute amounts of NPY are also normally expressed in dentate granule cells, while seizure activity in rats induces robust NPY expression in granule cells. Y1 and Y2 receptors are the most abundant NPY receptors expressed in the dentate gyrus. Y1 receptors are postsynaptic receptors, primarily located on granule cell dendrites in the molecular layer and some interneurons, while Y2 receptors are presynaptic receptors mediating inhibition of glutamate release, and potentially that of NPY and GABA depending on their presynaptic localization, and may also be expressed on some hilar interneurons. In humans, monkeys and mice, Y2 receptors are also present on mossy fibers, but not in most rat species, though functional evidence suggests their presence. Hilar interneurons containing NPY degenerate in temporal lobe epilepsy and in Alzheimer's disease and reduced levels of NPY in dentate hilus are associated with depression. By activating Y1 receptors, NPY also exerts powerful neuroproliferative effects on subgranular zone progenitor cells, increasing the number of newly born granule cells in the adult dentate gyrus. Functionally, NPY exerts anticonvulsive actions mediated by Y2 receptors at mossy fiber terminals, but there are no presynaptic responses to NPY at perforant path inputs to dentate granule cells in rats or mice. NPY also has potentially complicated actions on NPY-containing interneurons. Elevated expression of NPY in mossy fibers of the rat, sprouting of NPY interneurons in the human dentate, and over-expression of Y2 receptors in mossy fibers indicate an anticonvulsive role of endogenous NPY in epilepsy. However, the physiological role of NPY in the healthy dentate gyrus remains unclear.
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PMID:Neuropeptide Y in the dentate gyrus. 1776 25

Neuropeptide Y (NPY) has been shown to depress the hyperexcitability of neurons. In the present study, we investigated the association between the nucleotide (nt) 5671 C/T polymorphism of the NPY gene and the plasma NPY level in patients with febrile seizures (FS). Fifty-six patients with FS and 55 control subjects were enrolled. Genotype and allele frequencies were compared. The frequencies of genotypes TT, TC and CC for the NPY gene nt 5671 C/T polymorphism were 21.4%, 28.6% and 50.0%, respectively, in patients with FS, and 14.6%, 40.0% and 45.4%, respectively, in control subjects. The frequencies of alleles T and C were 35.7% and 64.3%, respectively, in patients with FS, while those in the control group were 34.5% and 65.5%, respectively. We found no significant relationship between the NPY gene nt 5671 C/T polymorphism and FS. The plasma NPY concentrations of the FS group, the age-matched non-FS group, and subjects aged > 6 years in the non-FS group were 48.23 +/- 32.49, 55.36 +/- 23.12, and 70.10 +/- 60.31 pg/mL, respectively. These results indicate no statistical difference in plasma NPY concentration between FS patients and the non-FS group. However, plasma NPY concentration was found to increase significantly with age.
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PMID:Neuropeptide Y gene polymorphism and plasma neuropeptide Y level in febrile seizure patients in Taiwan. 1805 4

Neuropeptide Y (NPY) gene transduction of the brain using viral vectors in epileptogenic regions can effectively suppress seizures in animals, and is being considered as a promising alternative treatment strategy for epilepsy. Therefore, it is fundamental to understand the detailed mechanisms governing the release and action of transgene NPY in neuronal circuitries. Using whole-cell recordings from subicular neurons, we show that in animals transduced by recombinant adeno-associated viral (rAAV) vector carrying the NPY gene, transgene NPY is released during high-frequency activation of CA1-subicular synapses. Released transgene NPY attenuates excitatory synaptic transmission not only in activated, but also in neighboring, non-activated synapses. Such broad action of transgene NPY may prevent recruitment of excitatory synapses in epileptic activity and could play a key role in limiting the spread and generalization of seizures.
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PMID:Activity-dependent volume transmission by transgene NPY attenuates glutamate release and LTP in the subiculum. 1865 99

Febrile convulsion (FC) is the most common neurological disease in children. Cases with seizures that persist for more than 15 minutes or recurrent seizures within the same febrile illness are considered to be atypical and may have a different prognosis. Neuropeptide Y (NPY), an endogenous anticonvulsant that is widely distributed throughout the central nervous system, including the hippocampus, is known to prevent seizures by increasing the seizure threshold. Based on our previously finding that patients with atypical FC have lower concentrations of NPY, we hypothesized that the concentration of NPY may play a role in the development of atypical FC. To investigate this hypothesis, we used a radioimmunoassay to measure the plasma NPY concentration of 60 children with FC (typical FC, n = 46; atypical FC, n = 14) and 56 age-matched controls. The atypical FC group had significantly lower concentrations of NPY than children with typical FC and controls (66.47 +/- 19.11 pmol/L vs. 88.68 +/- 28.50 pmol/L and 86.82 +/- 22.66 pmol/L, respectively). Very low NPY levels were found in two patients; one patient (NPY level: 44.75 pmol/L) experienced prolonged seizures lasting for up to 1 hour and the other had recurrent seizures (three seizures) during the same febrile illness (NPY level: 33.53 pmol/L). These results suggest that patients with inadequate NPY inhibitory activity are more susceptible to atypical FC.
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PMID:Lower plasma neuropeptide Y level in patients with atypical febrile convulsions. 2004 Apr 67

Neuropeptide Y (NPY) is an endogenous peptide with powerful anticonvulsant properties. Its overexpression in the rat hippocampus, mediated by the local application of recombinant adeno-associated viral (rAAV) vectors carrying the human NPY gene, results in significant reduction of seizures in acute and chronic seizure models. In this study, we characterized a more efficient rAAV-NPY vector to improve cell transfection in the injected area. The changes included pseudotyping with the AAV vector serotype 1 (rAAV1), and using the strong constitutive hybrid CBA promoter, which contains a cytomegalovirus enhancer and chicken beta-actin promoter sequences. We compared NPY expression and the associated anticonvulsant effects of this new vector, with those mediated by the former rAAV vector with chimeric serotype 1/2 (rAAV1/2). In addition, we investigated whether rAAV serotype 1 vector-mediated chronic NPY overexpression causes behavioural deficits that may detract from the clinical utility of this therapeutic approach. We report that rAAV-NPY serotype 1 vector has significantly improved anticonvulsant activity when compared with serotype 1/2 vector, as assessed by measuring EEG seizure activity in kainic acid treated rats. rAAV1-mediated NPY overexpression in naive rats did not result in alterations of physiological functions such as learning and memory, anxiety and locomotor activity. In addition, we did not observe glia activation, or humoral immune responses against serotype 1 vector, which could inactivate gene expression. Our findings show that rAAV1-NPY vector with the CBA promoter mediates powerful anticonvulsant effects and seems to be safe in rodents, thus it may be considered a vector of choice for possible clinical applications.
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PMID:Anticonvulsant effects and behavioural outcomes of rAAV serotype 1 vector-mediated neuropeptide Y overexpression in rat hippocampus. 2022 Jul 82


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